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Background:  Progression rates from the initial HIV infection to advanced AIDS vary significantly among infected individuals and depend on multiple viral and host factors.  Here, we analyzed a group of atypical long-term non-progressor (LTNP) patients with stable CD4⁺ cell counts but persistent high levels of plasma viremia for more than 10 years, in the absence of antiretroviral treatment.

Methods:  HIV-1 isolates were obtained from 4 viremic LTNP (V-LTNP) patients. Viral isolates from 3 slow-progressors (SP) and 1 typical-progressor individual were used as a control. HIV-1 replicative fitness was evaluated using viral growth kinetics and growth competition experiments, followed by a real-time polymerase chain reaction (PCR) assay. HIV-1 genomic regions previously associated with long-term survival (i.e., lymphoproliferative rersponse (LTR), pol, vpr, env, and nef) were PCR amplified and sequenced.

Results:  V-LTNP and SP patients had been infected for >10 years (range 10 to17 years), with a mean CD4⁺ cell count of 518 (range 442 to 619) and 400 (range 260 to 483), respectively. Moreover, V-LTNP had a less-marked decline in CD4⁺ cells (mean of 0.91, range 0.4 to -1.94 CD4⁺/month) than SP (mean -10.3, range -8.2 to -13.1 CD4⁺/month). Interestingly, V-LTNP carried viruses with impaired replicative fitness, contrary to HIV-1 isolates from the SP and typical progressor patients. Although genotypic analyses showed no major defects in any of the viral genes analyzed, two HIV-1 isolates from V-LTNP patients had unusual mutations in the long-term repeat (LTR)--i.e., single deletions in the bulge of transaction response element (TAR) and/or the second NF-κB binding site, or the absence of 1 Sp1 binding site).  Seven out of 8 viruses had the R77Q mutation in vpr, which has been associated with slow disease progression; however, 2 of these had additional mutations (amino acid insertions) in the carboxyl end of the protein.

Conclusions:  Intrinsic viral characteristics have been associated with delayed progression to AIDS, particularly in LTNP individuals. We analyzed a subset of LTNP patients with atypical high viremia and demonstrated that similar to the phenomenon observed in patients with a “discordant response” to antiretroviral therapy (i.e., high CD4⁺ cell counts with detectable viral load), reduced viral replicative fitness seems to correlate with late disease progression in untreated individuals.

Keywords: long-term non-progressor; fitness; disease progression